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The Cardioprotection of the Insulin-Mediated PI3K/Akt/mTOR Signaling Pathway

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Abstract

Apoptosis occurs frequently in myocardial infarction, oxidative stress injury, and ischemia/reperfusion injury, and plays a pivotal role in the development of heart diseases. Inhibition of apoptosis alone does not necessarily lead to meaningful rescue in terms of either cardiomyocyte survival or function. Activation of the PI3K/Akt signaling pathway induced by insulin not only inhibits cardiomyocyte apoptosis but also substantially preserves and even improves regional and overall cardiac function. Insulin can protect cardiomyocytes from apoptosis by regulating a number of signaling molecules, such as eNOS, FOXOs, Bad, GSK-3β, mTOR, NDRG2, and Nrf2, through activating PI3K and Akt. This review focuses on the protective mechanisms and targets of insulin identified in the prevention and treatment of myocardial injury.

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Abbreviations

AGEs:

Advanced glycation end products

ARE:

Antioxidant responsive element

CNT1 and CNT2:

Concentrative nucleoside transporter 1 and 2

4E-BP1:

Eukaryotic initiation factor 4E binding protein 1

eIF4E:

Eukaryotic initiation factor 4E

eNOS:

Endothelial nitric oxide synthase

ENT2:

Equilibrative nucleoside transporter 2

FKBP12:

FK506-binding protein

FOXOs:

Forkhead transcription factors

GPCRs:

Seven transmembrane G protein-coupled receptors

GSK-3β:

Glycogen synthase kinase-3β

HO-1:

Heme oxygenase 1

IGF-1:

Insulin-like growth factor-1

IGF-1R:

IGF-1 receptor

ILK:

Integrin-linked kinase

IPC:

Ischemic preconditioning

I/R:

Ischemia/reperfusion

IRS-1:

Insulin receptor substrate-1

IRSs:

Insulin receptor substrates

mPTP:

Mitochondrial permeability transition pore

mTOR:

Mammalian target of rapamycin

mTORC1/2:

mTOR complexes 1/2

NDRG2:

N-myc downstream-regulated gene 2

NFAT3:

Calcineurin-related nuclear factor activation transcription 3

Nrf2:

Transcription factor-E2-related factor 2

PDK1:

Phosphoinositide-dependent kinase-1

PH:

Pleckstrin homology

PHLPP:

PH domain and leucine rich repeat protein phosphatases

PIKK:

Phosphatidylinositol kinase-like kinases

PI3K/Akt:

Phosphoinositide 3-kinase/protein kinase B

PIP3:

Phosphatidylinositol (3, 4, 5)-triphosphate

PIP2:

Phosphatidylinositol (4, 5)-bisphosphate

PP2A:

Protein phosphatase 2A

PTEN:

Phosphatase and tensin homolog deleted on chromosome 10

ROS:

Reactive oxygen species

RTK:

Receptors tyrosine kinases

SHIP:

SH2 domain-containing inositol-polyphosphate 5′-phosphatase

S6K1:

p70 S6 kinase 1

VEGF:

Vascular endothelial growth factor

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Acknowledgments

The authors thank Shile Huang (Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, USA) for having the manuscript edited. This work was supported by grants from the Natural Science Foundation of Shandong Province (No. ZR2013HM084) and the Independent Innovation Foundation of Shandong University (No. 2012ZD043) of the People’s Republic of China.

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The authors declare that they have no conflicts of interest.

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Authors and Affiliations

  1. Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan, 250012, Shandong, China

    Hong Yao & Xiuzhen Han

  2. Pharmaceutical Preparation Section, Hospital of Laiwu Steel Group, Laiwu, 271126, Shandong, China

    Xiangyang Han

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  1. Hong Yao
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  2. Xiangyang Han
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  3. Xiuzhen Han
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Correspondence to Xiuzhen Han.

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Yao, H., Han, X. & Han, X. The Cardioprotection of the Insulin-Mediated PI3K/Akt/mTOR Signaling Pathway. Am J Cardiovasc Drugs 14, 433–442 (2014). https://doi.org/10.1007/s40256-014-0089-9

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  • DOI: https://doi.org/10.1007/s40256-014-0089-9

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